Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.S(=[N:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)=O>N1C=CC=CC=1>[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]2=[O:8])=[O:24])=[CH:21][CH:20]=1
Reactant: O=S=Nc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCCCCN1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)N2CCCCCC2=O)cc1
Temperature: 0 °C
Yield: 68 %

Procedure:
A three liter-volume three-necked flask was charged with 144 g (1.27 mol) of caprolactam, 2 liters of toluene and 1 liter of pyridine, and the content was stirred at 0° C. under a nitrogen gas atmosphere. Then 256.5 g (1.27 mol) of p-sulfinylaminobenzoyl chloride, synthesized in Synthesis Example 1, was added into the flask, and the mixture was gently stirred until the temperature reached room temperature. Thereafter the content was stirred for 14 hours to conduct a reaction. Pyridine hydrochloride, thus precipitated, was filtered and the filtrate was washed twice with aqueous 5% sodium hydrogencarbonate. The solvent was distilled off under a reduced pressure from the organic phase to afford a white residue. The white residue was twice recrystallized from ethyl acetate to give N-(p-aminobenzoyl)caprolactam having a melting point of 156°-158° C. in a yield of 68%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Br)ccc1-n1ccnc1
Yield: 73.7 %

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (1.12 mL; 9.09 mmol; 1 eq) and diisopropylethylamine (1.58 mL; 9.09 mmol; 1 eq;) in anhydrous acetonitrile (80 mL) is added imidazole (620 mg; 9.09 mmol; 1 eq) under argon. The reaction mixture is allowed to stir under reflux for 65 hours until complete consumption of starting material. The crude mixture is concentrated under vacuum and the resulting powder dissolved in ethyl acetate (60 mL). The organic phase is then washed with water (50 mL), brine (50 mL) and dried over sodium sulfate to provide an orange powder after concentration under vacuum. Further purification by flash chromatography on silica gel (ethyl acetate/cyclohexane 9:1) afforded the title compound (1.81 g; 6.7 mmol; 74%) as an orange powder.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7].[OH-].[K+].CN(C)[CH:26]=[O:27]>>[CH2:6]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([CH:26]=[O:27])=[CH:13][C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:7]
Reactant: CCN1c2ccccc2Sc2ccccc21
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1c2ccccc2Sc2cc(C=O)ccc21
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (POCl3,3.7 ml, 0.04 mol) was added dropwise to 4.4 ml (0.06 mol) of dry dimethylformamide (DMF) at 0° C. under a nitrogen atmosphere. This solution was warmed up slowly to room temperature. Then, a solution of 5 g (0.02 mol) of 10-ethylphenothiazine in dry DMF was added dropwise. The reaction mixture was refluxed at 80° C. for 24 hours and poured into the ice water. This solution was neutralized with potassium hydroxide until the pH reached 6–8. The product was extracted with chloroform. The chloroform extract was dried with anhydrous sodium sulfate, filtered and distilled. The product was crystallized from methanol. The yield of 10-ethylphenothiazine-3-carbaldehyde (C15H13NOS, FW=255.34) was 65%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:16](O)[CH2:17][OH:18].O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:15]1[CH:14]=[CH:13][CH:12]=[N:11][C:10]=1[C:5]1([C:8]#[N:9])[CH2:6][CH2:7][C:2]2([O:18][CH2:17][CH2:16][O:1]2)[CH2:3][CH2:4]1
Reactant: OCCO
Reactant: N#CC1(c2ncccn2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: N#CC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of 4-oxo-1-(pyrimidin-2-yl)cyclohexanecarbonitrile (333 mg, 1.66 mmol), ethylene glycol (96.9 μl, 1.74 mmol), and p-toluenesulfonic acid monohydrate (15.7 mg, 82.7 μmol) in benzene (10 mL) was refluxed for 1.5 h while the water formed during the reaction was removed azeotropically using a Dean-Stark apparatus. After being cooled down to room temperature, the reaction was diluted (Et2O) and washed (2×H2O, 2×sat aqueous NaHCO3, and 2× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 40-50% EtOAc/Hexanes, gradient elution) gave 8-pyrimidin-2-yl-1,4-dioxa-spiro[4,5]decane-8-carbonitrile (325 mg, 1.33 mmol, 80%) as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH:11][CH2:12][C@@H:13]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[C:22](S(CCC)(=O)=O)[N:21]=2)=[C:18]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:17]=[CH:16]1)[CH3:14]>C1COCC1>[OH:11][CH2:12][C@@H:13]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:10][C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[N:21]=2)=[C:18]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:17]=[CH:16]1)[CH3:14]
Reactant: Oc1ccc(F)cc1
Reactant: CCCS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@@H](C)CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](CO)n1cnc(-c2ccc(F)cc2)c1-c1ccnc(Oc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (95%) (252 mg, 10 mmol) was added in small portions to absolution of 4-fluorophenol (2.21 g, 19.8 mmol) in dry THF (50 mL). After the vigorous reaction had subsided, this solution was added to a solution of the product of example 1 (g) (2 g, 4.95 mmol) dissolved in dry THF (200 mL). The reaction mixture was stirred at rt under argon for 1 h. The reaction mixture was concentrated, and the residue partitioned between EtOAc and H2O. The organic phase was washed with 1N NaOH, brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (silica gel, 0–4% MeOH/CH2Cl2) to give the title compound as a light yellow solid. ES (+) MS m/e=409 (MH+)
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[N:27]=[N:28][N:29]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH:30]=4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[N:27]=[N:28][N:29]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH:30]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-c3cn(C4CCCC4)nn3)cnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CCN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cn(C5CCCC5)nn4)nc23)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of 2-(1-cyclopentyl-1H-[1,2,3]triazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (85 mg, 0.14 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL). The reaction mixture was stirred at room temp for 3 h then concentrated. The residue was redissolved in CH2Cl2 (4 mL) and ethylenediamine (0.5 mL) was added. The reaction mixture was stirred at room temp for 0.5 h then concentrated. The residue was purified twice by silica gel chromatography (50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc then 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH)) then triturated with Et2O to isolate 35 mg (52%) of 2-(1-cyclopentyl-1H-[1,2,3]triazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a white powder. MS: (M+H)+=488.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=1)=[O:24]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:30]3[CH:31]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:27]=[N:28][CH:29]=3)[CH2:33][CH2:34]2)=[O:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cncc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cncc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 170 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2-methyl-N-[5-(4-piperidinyl)-3-pyridinyl]propanamide according to the procedures described in Scheme 14: 1H NMR (400 MHz, CDCl3) δ 8.47–8.42 (m, 1 H), 8.21–8.16 (m, 1 H), 8.09 (s, 1 H), 7.59 (s, 1 H), 7.35–7.20 (m, 10 H), 6.87 (s, 1 H), 4.91 (s, 1 H), 3.46–3.36 (m, 2 H), 3.01–2.92 (m, 2 H), 2.62–2.47 (m, 2 H), 2.47–2.37 (m, 2 H), 2.11–1.94 (m, 4 H), 1.86–1.59 (m, 4 H), 1.25 (d, 6 H, J=7.2 Hz); ESMS m/e: 499.4 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[CH3:19][N:20]([CH3:37])[CH2:21][CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH2:22][CH2:21][N:20]([CH3:37])[CH3:19])[C:24]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: OC(c1ccccc1)c1ccc(OCCCl)cc1
Reactant: CCOC(=O)c1cc2ccccc2n1CCN(C)C
Product: CCOC(=O)c1c(C(c2ccccc2)c2ccc(OCCCl)cc2)c2ccccc2n1CCN(C)C
Yield: 81.3 %

Procedure:
Substantially the same procedure as in Reference Example 5 was repeated using 4-(2-chloroethoxy)benzhydrol (17.66 g, 67.2 mmol) and ethyl 1-(2-dimethylaminoethyl)indole-2-carboxylate (19.2 g, 73.9 mmol) to give 27.6 g (yield: 81%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C.CN(C)[CH:25]=[O:26]>>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([O:26][CH3:25])=[O:9]
Reactant: OCc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: COC(=O)c1cncc(Br)c1

Procedure:
5-Bromo-3-hydroxymethylpyridine (3.41 g), imidazole (13.33 g), t-butyldimethylchlorosilane (13.57 g) and N,N-dimethylformamide (63 ml) were treated as reported in J. Am. Chem. Soc., 6190 (1972) to give the title compound (5.605 g) as a yellow oil (yield: quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[CH3:25][O:26][N:27]=[C:28]1[C:32]2([CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)[CH2:31][NH:30][CH2:29]1.C(#N)C>C(N(CC)CC)C>[C:39]([O:38][C:36]([N:34]1[CH2:35][C:32]2([C:28](=[N:27][O:26][CH3:25])[CH2:29][N:30]([C:16]3[CH:17]=[C:18]4[C:13]([C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10][N:9]4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:14][C:15]=3[F:20])[CH2:31]2)[CH2:33]1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)CC12CN(C(=O)OC(C)(C)C)C2
Reaction time: 4 h
Yield: 67.8 %

Procedure:
1-(2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 120 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 400 mg of Amberlite® IRA-420 were added to 10 ml of acetonitrile and thereto 0.5 ml of triethylamine was added by dropping. The resulting mixture was refluxed for 48 hours and thus precipitated solid was filtered off. To the filtrate 5 ml of ethylether was added and the resulting mixture was stirred for 4 hours. The precipitated solid was filtered and dried to give 110 mg of the titled compound(yield: 67.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16](Br)=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[CH3:29][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([CH3:29])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2Cc2ccccc2)c1OC(C)=O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c(C)cn2Cc2ccccc2)c1OC(C)=O

Procedure:
Prepared in analogy to a Stille methylation step in the Example 103(b) from 4-acetoxy-1-benzyl-3-bromo-7-cyano-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, tetramethyl tin, and Pd(PPh3)2Cl2. The title compound, ESI MS (m/z): 378 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[NH:25]1[CH2:30]C[O:28]CC1.[OH-:31].[Na+].Cl>O1CCOCC1>[N:11]1([C:30]([NH2:25])=[O:31])[CH2:10][CH2:5][O:4][CH2:3][CH2:20]1.[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16]([OH:28])(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: C1COCCN1
Reactant: [OH-]
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)O)cc1Oc1ccc(Cl)cc1Cl
Product: NC(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.36 g, 3.2 mmol) was dissolved in dioxan (5 ml) and at 0° C. added dropwise to a solution of morpholine (2.25 ml, 25.6 mmol) in 1N aqueous NaOH (26 ml, 26 mmol) and dioxan (20 ml). The mixture was stirred for 1 hour at 0° C., acidified with 1N HCl and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvent was evaporated off. The residue was purified by chromatography (silica gel, CH2Cl2 /ethyl acetate 9/1). Yield: 0.93 g=60% 13C (100 MHz, DMSO-d6) δ 150.02, 147.15, 133.44, 130.43, 129.51, 129.31, 129.18, 126.23, .125.98, 123.95, 123.02, 122.51, 116.78, 115.83, 65.41, 45.83, 41.03
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:48]([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][C:56]1[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[C:57]=1[C:58]([O:60][CH3:61])=[O:59])=[O:49])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:33])[C:17](=[O:25])[C:18]([O:20]C(C)(C)C)=[O:19])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].C1(C=CC=C(O)C=1)O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:48]([NH:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][C:56]1[CH:65]=[CH:64][CH:63]=[C:62]([OH:66])[C:57]=1[C:58]([O:60][CH3:61])=[O:59])=[O:49])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]([C:17]([C:18]([OH:20])=[O:19])=[O:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([OH:34])=[O:33])=[CH:14][CH:15]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cccc(O)c1C(=O)OC
Agent: Oc1cccc(O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)O)c2ccccc2C(=O)O)cc1)C(=O)NCCCCOc1cccc(O)c1C(=O)OC
Yield: 52 %

Procedure:
A mixture methyl 2-{4-[(N-[(allyloxy)carbonyl]-4-{{2-[(benzhydryloxy)carbonyl]phenyl}[tert-butoxy(oxo)acetyl]amino}-L-phenylalanyl)amino]butoxy}-6-hydroxybenzoate (89 mg, 0.10 mmol), 20 mg of resorcinol, and trifluoroacetic acid (1.5 mL) in methylene chloride (2.0 mL) was stirred for 5 hours, concentrated under reduced pressure. The crude product was purified on a Gilson preparative HPLC to provide the titled compound as a white powder (35 mg, 0.052 mmol, 52%). MS (ESI+) m/e 678 (M+H)+, 1H NMR (300 MHz, DMSO-d6) 1.40-1.66 (m, 4H), 2.68-2.83 (m, 1H), 2.83-2.98 (m, 1H), 2.98-3.15 (m, 2H), 3.72 (s, 3H), 3.90 (t, J=5.85 Hz, 1H), 4.09-4.12 (m, 1H), 4.33-4.41 (m, 2H), 5.08 (d, J=10.8 Hz, 1H), 5.18 (d, J=18.0 Hz, 1H), 5.70-5.90 (m, 1H), 6.47 (d, J=8.7 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.38-7.66 (m, 3H), 7.93-8.03 (m, 2H), 9.92 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[CH:7]1[C:6]([C:10]([NH2:15])=[O:12])=[CH:5][C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8.06 gm (50 mMol) indole-5-carboxylic acid in 150 mL dimethylformamide were added 8.11 gm (50 mMol) carbonyldiimidazole and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was then added dropwise to 150 mL concentrated ammonium hydroxide and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to give a viscous oil which was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing 0-10% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give the title compound as an oil which crystallizes upon standing.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][CH:4]([Cl:12])[C:5]([O:7][CH2:8][C:9](Cl)=[O:10])=[O:6].O>C(Cl)Cl>[CH3:1][NH:2][C:9](=[O:10])[CH2:8][O:7][C:5](=[O:6])[CH:4]([Cl:12])[Cl:3]
Reactant: CN
Reactant: O=C(Cl)COC(=O)C(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CNC(=O)COC(=O)C(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution was made by combining while cooling in an ice bath, 2.33 g (0.03 mole) of a 40% aqueous solution of methylamine and 100 ml of methylene chloride. A second solution containing 3.08 g (0.015 mole) dichloroacetoxyacetyl chloride dissolved in 5 ml methylene chloride was slowly added to the first solution. The mixture was stirred in the ice bath for one half hour. After remaining at room temperature for one hour, it was refluxed for ten minutes and cooled again. The reaction product was water washed twice and dried over magnesium sulfate. It was decolorized with a decolorizing agent and charcoal. The solvent was removed by reduced pressure evaporation and oil pumped. A semi-solid consisting of 1.5 g (50% yield) of N-methyl dichloroacetoxyacetamide was obtained. The structure was confirmed by infrared spectraphotometric analysis (IR).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19](O)=[C:18]([CH3:23])[CH:17]=1)(=[O:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12](=[O:14])[CH3:13])=[CH:17][C:18]=1[CH3:23]
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: CC(=O)Oc1ccc(O)c(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(O[C@H](CCCl)c2ccccc2)c(C)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A solution of (S)-(−)-3-chloro-1-phenyl-1-propanol (0.204 gm, 1.20 mMol), 4-acetoxy-2-methylphenol (0.200 gm, 1.20 mMol) and triphenylphosphine (0.346 g, 1.32 mMol) in 10 mL tetrahydrofuran was cooled to 0-5° C. under argon. This mixture was treated dropwise with di-isopropylazodicar-boxylate (0.26 mL, 1.32 mMol) in tetrahydrofuran (2 mL). The resulting mixture was stirred for 1 hour at 0-5° C. and was then allowed to warm to room temperature. After stirring at room temperature over night the reaction mixture was concentrated under reduced pressure and the residue triturated with 10% ethyl acetate in pentane and stirred until the suspended solid was crystalline. The suspension was filtered and the recovered crystalline solid washed with 10% ethyl acetate in pentane. The combined filtrates were concentrated under reduced pressure and the residue subjected to silica gel chromatography eluting with toluene. Fractions containing product were combined and concentrated under reduced pressure to provide 0.205 gm (54%) of the desired compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]([F:23])([F:22])[S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([S:14][C:13]([Cl:12])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(SC(F)(F)Cl)cc1
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and 4-((chloro-difluoromethyl)thio)aniline (Stage 217.3) to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.78 min, UPLC-MS (Condition 3) tR=1.32 min, m/z=425 [M−H]−.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].OC1C=CC=CN=1>CO>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(C)CCN
Agent: Oc1ccccn1
Solvent: CO
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A suspension of methyl 4-(4-biphenylylmethoxy)phenylacetate (2.00 g), N,N-dimethylethylenediamine (1.60 g), 2-hydroxypyridine (573 mg) in methanol (4.0 ml) was heated under reflux under nitrogen for 16 hr and cooled until the temperature of the reaction mixture reached to 60±2° C., to which methanol (8.0 ml) was added. The reaction mixture was heated under reflux for additional one hr and cooled to room temperature. The precipitate was collected by filtration and washed with methanol (4.0 ml to obtain the titled compound (2.18 g).